Harshita Kumari

Controlling the Self‐Assembly of Metal‐Seamed Organic Nanocapsules

The advent of modern molecular characterization techniques in the mid 20th century brought about a renaissance in our understanding of life s many processes. Notably, the structural determination of large biomolecules through the development of techniques such as NMR spectroscopy and X-ray diffraction (XRD) has given scientists valuable insight into the inner workings of cells. Many of these molecules are highly symmetrical, multicomponent entities, though determining the processes by which they assemble has been a difficult task. The biosynthesis of DNA, for example, came much later than its structural characterization by Watson and Crick. It is exactly this knowledge, however, that allows one to control the system. Supramolecular chemists have likewise endeavored to control the self-assembly processes in multicomponent entities. Although simpler than many biomolecules, the size and complexity of the macromolecules that embody this field largely preclude the use of standard mechanistic analyses that are applicable to smaller compounds. Our work has focused on metal-seamed pyrogallol[4]arene (PgC) nanocapsules. Forming rapidly through selfassembly, these large entities are composed of 2 or 6 macrocyclic units that act as chelates through their upper rims for 8, 12, or 24 metal ions (Figure 1). It is important to note that the 6-macrocycle, 24-metal ion hexameric nanocapsule results from the remarkable self-assembly of 30 entities. The dimeric or hexameric capsules are highly sym-

Solution structures of nanoassemblies based on pyrogallol[4]arenes.

Nanoassemblies of hydrogen-bonded and metal-seamed pyrogallol[4]arenes have been shown to possess novel solution-phase geometries. Further, we have demonstrated that both guest encapsulation and structural rearrangements may be studied by solution-phase techniques such as small-angle neutron scattering (SANS) and diffusion NMR. Application of these techniques to pyrogallol[4]arene-based nanoassemblies has allowed (1) differentiation among spherical, ellipsoidal, toroidal, and tubular structures in solution, (2) determination of factors that control the preferred geometrical shape and size of the nanoassemblies, and (3) detection of small variations in metric dimensions distinguishing similarly and differently shaped nanoassemblies in a given solution. Indeed, we have shown that the solution-phase structure of such nanoassemblies is often quite different from what one would predict based on solid-state studies, a result in disagreement with the frequently made assumption that these assemblies have similar structures in the two phases. We instead have predicted solid-state architectures from solution-phase structures by combining the solution-phase analysis with solid-state magnetic and elemental analyses. Specifically, the iron-seamed C-methylpyrogallol[4]arene nanoassembly was found to be tubular in solution and predicted to be tubular in the solid state, but it was found to undergo a rearrangement from a tubular to spherical geometry in solution as a function of base concentration. The absence of metal within a tubular framework affects its stability in both solution and the solid state; however, this instability is not necessarily characteristic of hydrogen-bonded capsular entities. Even metal seaming of the capsules does not guarantee similar solid-state and solution-phase architectures. The rugby ball-shaped gallium-seamed C-butylpyrogallol[4]arene hexamer becomes toroidal on dissolution, as does the spherically shaped gallium/zinc-seamed C-butylpyrogallol[4]arene hexamer. However, the arenes are arranged differently in the two toroids, a variation that accounts for the differences in their sizes and guest encapsulation. Guest encapsulation of biotemplates, such as insulin, has demonstrated the feasibility of synthesizing nanocapsules with a volume three times that of a hexamer. The solution-phase studies have also demonstrated that the self-assembly of dimers versus hexamers can be controlled by the choice of metal, solvent, and temperature. Controlling the size of the host, nature of the metal, and identity of the guest will allow construction of targeted host-guest assemblies having potential uses as drug delivery agents, nanoscale reaction vessels, and radioimaging/radiotherapy agents. Overall, the present series of solid- and solution-phase studies has begun to pave the way toward a more complete understanding of the properties and behavior of complex supramolecular nanoassemblies.

Exploring the magnetic behavior of nickel-coordinated pyrogallol[4]arene nanocapsules.

The magnetic behavior of nickel-seamed C-propylpyrogallol[4]arene dimeric and hexameric nanocapsular assemblies has been investigated in the solid state using a SQUID magnetometer. These dimeric and hexameric capsular entities show magnetic differentiation both in terms of moment per nanocapsule and potential antiferromagnetic interactions within individual nanocapsules. The weak antiferromagnetic behavior observed at low temperatures indicates dipolar interactions between neighboring nickel atoms; however, this effect is higher in the hexameric nickel-seamed assembly. The differences in magnetic behavior of dimer versus hexamer can be attributed to different coordination environments and metal arrangements in the two nanocapsular assemblies.

Ferrocene Species Included within a Pyrogallol[4]arene Tube

Research in host–guest complexes with ferrocene as a guest continues to attract attention. Macrocyclic hosts spanning from curcubiturils and cyclodextrins to resorcinarenes have been used to both encapsulate ferrocene and use as a component in nanometric frameworks. C-alkylpyrogallol[4]arenes (PgCs) are bowl-shaped compounds that are commonly used as building blocks in the construction of larger entities, such as capsules and nanotubes. Our work with C-methyl and C-heptylpyrogallol[4]arene has likewise shown that these compounds can function as hosts for ferrocene. The host–guest complex thus formed is a dimeric capsule with the enclosed and highly ordered ferrocene located between two PgC hemispheres. In addition to such capsular motifs, the conical shape of the calixarenes, resorcinarenes, and pyrogallolarenes can likewise lead to the formation of tubular solid-state structures. These often incorporate large nonsolvent molecules as part of the tubular framework. An excellent example of a PgC-based tubular framework that accommodates large nonsolvent molecules is the host–guest complex of Chexylpyrogallol[4]arene (PgC6) with pyrene. [9] In this complex, tetramers of PgC6 associate with one another through hydrogen bonding, whereas the pyrene molecules intercalate between the C-hexyl pendant arms of the PgC. This leads to two distinct regions within the structure: a hydrophilic tube that encloses guest solvents along with a hydrophilic tube that accommodates the pyrene. Herein, we describe a second host–guest complex of C-methylpyrogallol[4]arene (PgC1) and ferrocene that conforms to a tubular structural motif. In contrast to the capsular motif, a tubular hydrophobic cavity, rather than a capsular cage, is responsible for incarceration of the guest, whereas the hydroxyls of the PgC1 complexes along with polar solvent molecules form the long-range hydrogen-bonding superstructure. Slow changes in concentration of a PgC1 and ferrocene solution caused by evaporation led to the crystallization of this unique architecture. Methanolic solutions containing various ratios of PgC1 to ferrocene (with the concentration of ferrocene set at 10 3 molL ) were allowed to evaporate until crystallization was evident. At a 1:1 PgC1/ferrocene ratio, crystals of the previously reported dimeric product were the sole product. However, at ferrocene ratios of 6:1 or higher, two different crystal habits formed were found, with green needle-like crystals accompanying the dark blue prisms of the ferrocene dimer. X-ray diffraction analysis of the single crystal showed the dark green needles to be a novel tubular motif 1 featuring ferrocene “beads” in a hydrophobic cylinder of repeating trimers of PgC1. The tubular structure 1 (Figure 1) displays a complicated hydrogen-bonding arrangement of PgC1 complexes. Each tube consists of alternating units of 3 PgC1 complexes rotated by 608 relative to one another along the crystallographic C axis and a single ferrocene guest. The overall structure thus closely resembles a family of resorcinarene-based nanotubes described by Rissannen et al. However, in contrast to both the resorcinarene tubes and our previously reported

Solution-phase structures of gallium-containing pyrogallol[4]arene scaffolds.

The variations in architecture of gallium-seamed (PgC4Ga) and gallium-zinc-seamed (PgC4GaZn) C-butylpyrogallol[4]arene nanoassemblies in solution (SANS/NMR) versus the solid state (XRD) have been investigated. Rearrangement from the solid-state spheroidal to the solution-phase toroidal shape differentiates the gallium-containing pyrogallol[4]arene nanoassemblies from all other PgCnM nanocapsules studied thus far. Different structural arrangements of the metals and arenes of PgC4Ga versus PgC4GaZn have been deduced from the different toroidal dimensions, C–H proton environments and guest encapsulation of the two toroids. PGAA of mixed-metal hexamers reveals a decrease in gallium-to-metal ratio as the second metal varies from cobalt to zinc. Overall, the combined study demonstrates the versatility of gallium in directing the selfassembly of pyrogallol[4]arenes into novel nanoarchitectures.

Magnetic differentiation of pyrogallol[4]arene tubular and capsular frameworks.

The differences in magnetic properties of metal-based nanometric assemblies are due to distinct contributions from host-guest interactions, structural integrity, and magnetic interactions. To disentangle these contributions, it is necessary to control the self-assembly process that forms these entities. Herein we study the effect of host-to-guest ratios to identify remarkably different structural-magnetic contributions of C-methylpyrogallol[4]arene⊂ferrocene/(PgC1)2⊂Fc dimers vs (PgC1)3⊂Fc nanotubes. At low temperature, a weak anti-ferromagnetic alignment is observed, suggesting a weak dipolar interaction between Fc guest moieties within adjacent dimers or tubes. Also, differences are observed between magnetic atom occupancy as a function of guest (PgC1⊂Fc tube/dimer) versus magnetic atom occupancy within the framework wall (PgC3Ni hexamer/dimer). Identification of the role of the framework shape and metal-metal distances in the crystal lattice opens up unparalleled prospects for materials engineering.

Cocrystals of gabapentin with C -alkylresorcin[4]arenes

The synthesis of cocrystals of gabapentin (GBP) with resorcin[4]arenes (RsCn) with different tail lengths, C-hexylresorcin[4]arene (RsC6) and C-propylresorcin[4]arene (RsC3), is reported. The structural elucidations of the two cocrystals show differences in packing arrangements and host–guest interactions.

Solution structure of copper-seamed C-alkylpyrogallol[4]arene nanocapsules with varying chain lengths

The stability of copper-seamed C-alkylpyrogallol[4]arene hexamers with varying chain lengths in solution has been studied using small-angle neutron scattering (SANS). The progression in diameter of spherical capsules with increasing alkyl chain lengths of copper-seamed hexamers in solution suggests both robustness as well as a close correlation between the solid phase and solution phase structures.

Exploring the Ellipsoidal and Core–Shell Geometries of Copper-Seamed C-Alkylpyrogallol[4]arene Nanocapsules in Solution

Small-angle neutron scattering (SANS) studies were used to probe the stability and geometry of copper-seamed C-alkylpyrogallol[4]arene (PgC(n)Cu; n = 11, 13, 17) hexamers in solution. Novel structural features are observed at chain lengths greater than 10 in both solid and solution phase. Scattering data for the PgC(11)Cu and PgC(13)Cu in chloroform fitted as core-shell spheres with a total spherical radius of about 22.7 and 22.9 Å respectively. On the other hand, the scattering curve for the PgC(17)Cu hexamer at both 1% and 5% mass fractions in o-xylene did not fit as a discrete sphere but rather as a uniform ellipsoid. The geometric dimensions of the ellipsoid radii are 24 Å along the minor axis and 115 Å along the major axis. It is expected that an individual hexamer with heptadecyl chains would exhibit a uniform radius of ca. 24 Å. However, an approximate ratio of 1:5 between radii lengths for the minor axis and major axis is consistent with interpenetration of the heptadceyl chains of adjacent hexamers to form a single ellipsoidal assembly.

Solution-phase and magnetic approach towards understanding iron gall ink-like nanoassemblies.

The degradative oxidation of Leonardo da Vinci s oeuvre, the works of Galileo, and many other imperiled ancient manuscripts is, ironically, catalyzed by the very ink that was used to write them. Historical artifacts such as these are characterized by the extensive use of “iron gall ink”, an ink commonly used prior to the twentieth century. Regardless of the specific composition, iron gall inks are complexes of various polyphenolic gallic acids, a class of tannins, and ferric/ ferrous ions, along with other agents such as gypsum and gum arabic. In the interest of preserving such invaluable works of ancient prose, Fe complexes with polyphenolic compounds, such as gallic acid, catechin, ellagic acid and pyrogallol, have been extensively studied by IR, ESR, NMR, XANES and Mçssbauer spectroscopy. However, structural elucidation of these complexes has proven difficult. Our interest in this field stems from the difficulty in characterizing similar Fe-polyphenolic complexes, namely the complexes with the bowlshaped pyrogallol[4]arenes (PgCn, n = alkyl chain length). Compared to other PgC-transition metal capsular entities, which have been thoroughly studied and characterized by XRD, the structure of the PgCnFe complexes has largely remained a mystery, much like that of the chemically similar gall inks. Herein, we present a new approach towards the characterization of these unique complexes through the combination of solid-state magnetic and in situ neutron scattering methods. In our previous studies, solid-state properties aided our understanding of solution-phase behavior. For example, solid-state PgCnM entities (M = Zn, Cu, Ni, Co) are spherical, and our small-angle neutron scattering (SANS) experiments indicate that they retain that architecture when dissolved in non-polar solvents. In contrast, solid-state PgC4Ga and PgC4GaZn entities have rugby-ball and spherical shapes, respectively, which convert to toroids of different metric dimensions in solution. Thus, SANS allows differentiation between architectures of similar metric dimensions and between varying metric dimensions of similar architectures. 6] The current study addresses our three-fold interest in investigating solution structures of magnetically interesting self-assembled frameworks, obtaining solid-state insight from solution-phase studies and exploring the parameters that direct self-assembly. Specifically, the stability, elemental ratios and magnetic properties of Fe-containing C-alkylpyrogallol[4]arene (PgCnFe) nanoassemblies were examined. PgC1Fe or PgC3Fe was synthesized by mixing 4 equiv of Fe(NO3)3 with 1 equiv of PgCn and 14 equiv of C5H5N (Py) in a variety of solvent systems. The blue-black precipitates obtained could not be crystallized; thus, structural studies were conducted using SANS. The solid-state magnetic behavior of these entities was investigated using a SQUID magnetometer. The composition of these nanoframeworks was measured with prompt gamma activation analysis (PGAA). The PGAA results for solid-state PgC1Fe and PgC3Fe reveal C:Fe ratios of 27.8:1 and 28.5:1 and C:N ratios of 28.1:1 and 29.2:1, respectively (see Supporting Information). The 1:1 ratio between Fe and C5H5N-derived nitrogen agrees with the metal:Py ratios typically found in metal-seamed pyrogallol[4]arene dimeric host capsules. However, in contrast to the typical capsular metal:PgCn ratio of 4:1, the Fe:PgCn ratio was unexpectedly deduced to be 1.3:1. This ratio also differs from those for the tubular and dimeric PgC1 ferrocene (PgC1 Fc) hydrogen-bonded inclusion complexes, for which the Fc:PgC1 ratios are 1:3 and 1:2, respectively. [4c,7] In the SANS study, the [D6]DMSO-solubilized PgC1Fe (3% mass fraction) was measured on the NG7 30 m SANS instrument at the NIST Center for Neutron Research (NCNR) in Gaithersburg, MD and analyzed with IGOR Pro. The scattering length density (SLD) of PgC1Fe was calculated at the molar ratio of 1:1.3:1.3 (PgC1:Fe:Py) obtained from the PGAA results, and the scattering data was fitted to spherical, cylindrical and ellipsoidal models. The data analysis revealed distinct structural differences between previously investigated metal-seamed spherical nanoassemblies and the Fe-containing pyrogallol[4]arene nanoassemblies (Figure 1). The scattering for PgC1Fe was higher at low scattering angles (q) and fitted [*] Dr. H. Kumari, A. V. Mossine, Prof. C. A. Deakyne, Prof. J. L. Atwood Department of Chemistry, University of Missouri-Columbia 601 S. College Avenue, Columbia, MO 65211 (USA) E-mail: deakynec@missouri.edu atwoodj@missouri.edu